To understand how the brain perceives color, it is necessary to learn how the retina creates its visual signals from the incoming flux of light. It is known that three types of cone photoreceptors are the starting point for any color signals. The cone responses to light are passaged to retinal ganglion cells, and their axons leave the eye to provide input to the visual thalamus, which in turn informs the rest of the brain. At present, there is a major controversy over the chromatic structure of the receptive fields of the "midget" class of retinal ganglion cells. To signal color, the responses of different cone types must be compared. It is uncertain if the midget ganglion cells receive comparative input from only single cone types, or from cone mixtures. The options would lead to different color coding schemes at this stage of the visual system, and thus have important consequences for how color is thought to be processed at later stages. Because the midget ganglion cells comprise about 80% of the output from the retina, it is crucial to work out their true signaling properties. The main impediments to solving this problem have been the inability to identify and stimulate individual cones in the living retina. The goal of this proposal is to overcome these limitations and develop a retinal microstimulator that can visualize the cones in a living eye, identify their spectral type, and most importantly, stimulate single cones selectively and repeatably with colored light sources. State-of-the-art adaptive optics techniques will be used to image and track the cone mosaic. The design will incorporate several convergent, confocal optical trains for multiwavelength imaging, stimulation, and cone spectral identification. To verify that the system can deliver stimuli as intended and produce wavelength-specific responses from cones, neurophysiological experiments will be conducted to map the cone fields providing input to single neurons in the visual thalamus of a trichromatic primate. These experiments are the only means of validating the stimulus precision of the instrument, and will provide the empirical foundation necessary for any future studies conducted in humans. PUBLIC HEALTH RELEVANCE: A color retinal microstimulator with unprecedented control of photoreceptor- specific stimuli will benefit ophthalmologists and physiologists studying normal and diseased photoreceptor function, as well as those interested in the neural basis of color processing in the cerebral cortex. The instrument will offer the first opportunity for probing, at a cellular level, the physiological and perceptual changes associated with cone dystrophies and colorblindness. It will also be useful for testing the effectiveness of gene therapies being developed for retinal ciliopathies.